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Tuesday, January 10, 2012

Do we still not know what causes cancer? Part I

Many theories have been proposed for the causes of cancer. We were involved in some of this work, long ago, before molecular approaches were possible. We were present when various immunological and other theories were being displaced by a genetic theory, and that theory has been developed over the years. Cancer is an evolutionary as well as genetic phenomenon, but it's the evolution of genetic variation among cells within the body.

A few observations, too much to go into here but involving a fairly rare childhood eye cancer called retinoblastoma, led to the idea that one could inherit susceptibility mutations (variation in particular genes), but that that required waiting for other mutations to occur somatically, that is, in body cells as they divide throughout life. Three of the key bits of evidence were, first, that frankly inherited susceptibility seemed rather rare (and it still does, for most types of cancer), even if inherited variation contributes to risk. Second, it was shown by some clever early experiments that cancers are clones of cells within the affected person's body: the tumor began as a single 'transformed' cell. Third, the risk of cancer rises with age in a way that seemed consistent with waiting time distributions; that is, a person had to 'wait' until some single cell was transformed, to become the progenitor of the tumor as it grew and sometimes spread around the body (metastasized).

Together, these facts suggested that cancer was a multihit, mutational disease. It was a genetic disease because the progenitor cell was transformed by mutations. It was clonal in that this single cell led to the entire descendant set of cells that comprised the tumor. And it was multihit in the sense that many different mutations were required to transform a cell. This was the somatic mutation theory (SMT) of cancer, which is what we ourselves worked on when we were in Texas long ago. The idea is that cancer is a disorder of the cell itself, a damaged cell that did not behave properly in its context.

The age pattern of cancer--how fast risk increased with age--could be associated with the type of tissue. Carcinomas grow in dividing tissue. In most organs, partly differentiated stem cells divide and become terminally differentiated for their type of tissue (stomach, intestine, etc.). When the differentiated cells died or were sloughed of, the stem cell would divide and produce more terminally differentiated cells. The tissue maintained its integrity because the cells had the right genes expressed, receptors on their surface, and so on, to behave properly for their type of tissue. Stem cells were normally quiescent until stimulated to divide. Somatic mutation released that inhibition and disrupted the orderly responsiveness, leading to the relatively undisciplined proliferation that is cancer.

The more stem cells at risk in a given tissue type, and the more their natural pattern involved dividing and differentiating, the faster risk would accumulate. If cells stopped dividing in a person's natural life-history, tumors became rarer and rarer as the person got older. The pattern was consistent, and the age-pattern of onset suggested that many mutational 'hits' were involved.

Work using techniques that became available mainly in the 1980s was consistent. Evidence of mutation in cancer cells compared to normal cells from the same individual implicated multiple different genes with (as in other complex traits), different sets of mutations in different tumors of the same type (lung, intestinal, etc.). At the same time, some of these mutations could be inherited, if the person had inherited a good copy of the gene along with a defective one. Then, one might have to wait for the bad-luck mutation of the other copy of that gene, along with some other genes. That's why even strong risk-affecting mutations don't cause cancer right away; instead, you have to wait less time for some other complement of mutations to arise.

It was clear that tumors were clones by and large, but as they grew and spread, new mutations, often involving unstable, multiple chromosomal changes, would arise so that the tumor itself then was comprised of a tree of varying descendant cells. When the right (for the cell, though for the victim, the wrong) set of mutations arose, some cells gained the ability to spread more rapidly, to invade other types of tissue, and so on. The more potent cells could out-compete the more sluggish ones, in a kind of selection. This became a kind of natural selection when drug therapy is applied, as some cells could survive the drug, leading to resistant tumors. The population of tumor cells were mutant but they were still the host's own cells, which explained why the immune system, structured to detect invading foreign cells, was not good at finding and removing them. Modern genetic analysis of tumor cells and normal cells has generally found evidence consistent with these ideas.

In this view, cancer is always a genetic disease and perhaps thus always amenable (in principle) to a genetic therapeutic approach: find the mutant gene and target cells expressing it in ways that are specific, so as to leave the same person's normal cells unaffected.

This was, then, an evolutionary theory of cancer involving genetic changes in somatic cells, complemented perhaps with some inherited mutations. It had most of the elements of Darwinian organismal evolution, including its basis in genes. It fit the epidemiology, including the role of environmental factors--largely being those that induced mutations or stimulated cell division. It is a theory we worked on, wrote about, and believed seemed consistent with the evidence (including, yes, GWAS studies of cancer, and various cancer genome projects!). We even suggested somatic polygenic models of evolution among body cells as consistent with the age-onset patterns.

But this theory has been questioned on a number of grounds, and there are, as usual, alternative explanations. These have been aired in a recent point-counterpoint in the May 2011 BioEssays in which the protagonists discuss serious questions about the somatic mutation theory of cancer. The facts discussed above may apply, but they may not account for all cases of cancer....or perhaps the data have been interpreted in the context of an assumed theory and hence seemed to be consistent with that theory.....a bias we often write about here on MT. Perhaps there are other kinds of causation.

We'll discuss those, as raised in the article, in our next post in this short series.

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